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EP0606336B1 - Process for making antimicrobial quinolonyl lactams - Google Patents

Process for making antimicrobial quinolonyl lactams Download PDF

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Publication number
EP0606336B1
EP0606336B1 EP92920743A EP92920743A EP0606336B1 EP 0606336 B1 EP0606336 B1 EP 0606336B1 EP 92920743 A EP92920743 A EP 92920743A EP 92920743 A EP92920743 A EP 92920743A EP 0606336 B1 EP0606336 B1 EP 0606336B1
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Prior art keywords
oxo
bond
carboxylic acid
hydrogen
alkyl
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German (de)
French (fr)
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EP0606336A1 (en
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Ronald Eugene White
Thomas Prosser Demuth, Jr.
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Warner Chilcott Pharmaceuticals Inc
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Procter and Gamble Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to processes for making antimicrobial compounds.
  • the compounds made by this invention contain, as integral substituents, a quinolone moiety and a lactam-containing moiety.
  • antimicrobial i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria.
  • antibacterials include a large variety of naturally-occurring (antibiotic), synthetic, or semi-synthetic compounds.
  • aminoglycosides ansamacrolides, beta-lactams (including penicillins and cephalosporins), lincosaminides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines, and sulfonamides.
  • antibacterials and other antimicrobials are described in Antibiotics, Chemotherapeutic and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition (1981).
  • QLAs Quinolony Lactam Antimicrobials
  • Manufacture of QLAs generally involves synthesis of suitably protected substituent beta-lactam and quinolone moieties, a linking process, and appropriate de-protection steps.
  • the specific linking process depends, of course, on the specific lactam and quinolone substituent moieties used, as well as the type of linkage desired.
  • Several such linking processes have been described in the literature.
  • EP-A-0,451,764 discloses carbapenem compounds and processes for their preparation. In particular, a reaction between phosgene and carbapenem alcohol at 0°C to room temperature is disclosed. However, the yields of these processes are often low, particularly for the preparation of QLAs having a penem substituent moiety.
  • the present invention encompasses methods for making certain QLAs. These compounds are useful for treating infectious disorders in humans or other animal subjects. Thus, the compounds made by this invention must be pharmaceutically acceptable. As used herein, such a "pharmaceutically-acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • QLAs pharmaceutically-acceptable
  • the compounds (“QLAS") made by the methods of this invention encompass any of a variety of lactam moieties linked, by a linking moiety, to a quinolone moiety at the 1-, 5-, or 7-position of the quinolone.
  • These compounds include those having the general formula [Q - L 1 ] - L - [L 2 - B] wherein Q, L', L, L 2 and B are as defined hereinabove.
  • Preferred antimicrobial compounds made by the processes of this invention include those where R3 is nil and comprises a bond to L 1 , and those where R 6 is nil and comprises a bond to L 1 .
  • Heteroatom is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.
  • Alkyl is a saturated hydrocarbon chain radical having from 1 to 8 carbon atoms, preferably from 1 to 4 carbon atoms.
  • Preferred alkyl groups include (for example) methyl, ethyl, propyl, isopropyl, and butyl.
  • Heteroalkyl is a saturated chain radical having from 3 to 8 members comprising carbon atoms and one or two heteroatoms.
  • Alkenyl is a hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond.
  • Carbocyclic ring is a saturated, unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
  • Cycloalkyl is a saturated carbocyclic ring radical.
  • Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl.
  • Heterocyclic ring is a saturated, unsaturated or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
  • Aryl is an aromatic carbocyclic ring radical.
  • Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl and naphthyl.
  • Heteroaryl is an aromatic heterocyclic ring radical.
  • Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, quinolinyl, pyrimidinyl and tetrazolyl.
  • Alkoxy is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl (i.e., -O-alkyl).
  • Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy.
  • Alkylamino is an amino radical having an alkyl substituent (i.e., -NH-alkyl).
  • Arylalkyl is an alkyl radical substituted with an aryl group.
  • Preferred arylalkyl groups include benzyl and phenylethyl.
  • Arylamino is an amine radical substituted with an aryl group (i.e., -NH-aryl).
  • Aryloxy is an oxygen radical having a aryl substituent (i.e., -O-aryl).
  • Preferred alkylacyl groups include (for example) acetyl, formyl, and propionyl.
  • Halo is a chloro, bromo, fluoro or iodo atom radical. Chloro and fluoro are preferred halides.
  • a “lower” hydrocarbon moiety is a hydrocarbon chain comprised of from 1 to 6, preferably from 1 to 4, carbon atoms.
  • a "pharmaceutically-acceptable salt” is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group.
  • Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium).
  • Preferred anionic salts include the halides (such as chloride salts).
  • a “biohydrolyzable ester” is an ester of a QLA that does not essentially interfere with the antimicrobial activity of the compounds, or that are readily metabolized by a human or lower animal subject to yield an antimicrobially-active quinolonyl lactam.
  • esters include those that do not interfere with the biological activity of quinolone antimicrobials or beta-lactam antimicrobials (cephems, for example). Many such esters are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987.
  • esters include lower alkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and alkyl acylamino alkyl esters (such as acetamidomethyl esters).
  • lower alkyl esters such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters
  • lactonyl esters such as phthali
  • substituent groups may themselves be substituted. Such substitution may be with one or more substituents.
  • substituents include (for example) those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).
  • Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
  • alkyl alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl
  • a particular radical may be defined for use as a substituent in multiple locations.
  • the R 8 substituent is defined as a potential substituent of R 7 , but is also incorporated into the definition of other substituents (such as R 1 , R 6 , and R 10 .
  • such a radical is independently selected each time it is used (e.g., R 8 need not be alkyl in all occurrences in defining a given compound of this invention).
  • Lactam-containing moiety
  • bonds "a” and "b” of formula (I) form any of a variety of lactam-containing moieties known in the art to have antimicrobial activity.
  • Such moieties wherein either bond “a” or bond “b” are nil (i.e., do not exist) are mono-cyclic; if both bonds exist, the structures are bi-cyclic.
  • bond "a” is a single bond and bond b" is a double bond.
  • Preferred lactam moieties include the oxacephems and carbacephems of the representative formula: wherein, referring to formula (II), bond "a” is a single bond; bond “b” is a double bond; R 12 is -C(R 8a )-, where R 8a is hydrogen; R 13 is -CH(R 33 ), where R 33 is COOH; and R 14 is -W'-C(R 8a )(R 38 )-C'"-R 37 , where R 8a and R 38 are hydrogen, R 37 is methylene, and W' is 0 (for oxacephems) or C(R 38 ) (for carbacephems).
  • lactam moieties include the isocephems and iso-oxacephems of the representative formula: wherein, referring to formula II, bond "a” is a single bond; bond "b” is a double bond; R 12 is -C(R 8a ) where R 8a is hydrogen; R 13 is -C(R 33 )-, where R 33 is COOH; and R 14 is -C(R 8a )(R 38 )-W-C"'-R 37 where R 8a and R 38 are each hydrogen, R 37 is methylene, and W is S (for isocephems) or O (for iso-oxacephems).
  • lactam-containing moieties include the penems, carbapenems and clavems, of the representative formula: wherein, referring to formula (II), bond "a” is a single bond; bond “b” is a double bond; R 12 is -C(R 8a ), where R 8a is hydrogen; R 13 is -C(R 33 )-, where R 33 is COOH; and R 14 is -W-C"'-R 37 , where R 37 is methylene, and W is S (for penems), C(R 38 ) (for carbapenems), or O (for clavems).
  • lactam moieties are described in the following articles: R.
  • lactam-containing moieties of this invention include the penicillins of the representative formula: wherein, referring to formula II, bond “a” is a single bond, bond “b” is a single bond; R 12 is -C(R 8a )-, where R 8a is hydrogen; R 13 is -CH(R 33 )- where R 33 is COOH; and R 14 , is -W-C"'(R 36 )-R 37 - where R 36 is methyl, R 37 is methylene, and W is S.
  • lactam-containing moieties include the monocyclic beta-lactams, of the representative formula: wherein, referring to formula (II), bond "a" is a single bond; bond "b” is-nil; R 12 is -C(R 8a )-, where R 8a is hydrogen; R 14 is nil; and R 13 is -SO 3 H (for a monobactam), -PO(OR 34 )OH (for a monophospham); -C(O)NHSO 2 N(R 34 )(R 35 ) (for a monocarbam), -OSO 3 H (for a monosulfactam), -CH(R 35 )COOH (for nocardicins), or -OCH(R 34 )COOH.
  • lactam moieties are described in C. Cimarusti et al., "Monocyclic 8-lactam Antibiotics", 4 Medicinal Research Reviews 1 (1984).
  • lactam moieties include the monocyclic beta-lactams of the representative formula: wherein referring to formula II, bond “a” is nil, bond “b” is a single bond; R 12 is -C(R 8a )(R 29 )- where both R 8a and R 29 are hydrogen; and R 14 is nil.
  • lactam moieties include the 2,3-methylenopenams and -carbapenams of the representative formula: wherein, referring to formula (II), bond "a” is a single bond; bond “b” is a single bond; R 12 is -C(R 8a )-, where R 8a is hydrogen; R 13 is -C*(R 33 ), where R 33 is COOH; and R 14 is W-C"'(R 36 )-R 37 , where R 37 is nil, R 36 is linked to C* to form a 3-membered carbocyclic ring, and W is C(R 38 ) or sulfur.
  • Lactam moieties of this invention also include the lactivicin analogs of the representative formula: wherein, referring to formula (II), bond “a” is nil; bond “b” is a single bond; R 12 is -CH 2 -R 32 , where R 32 is 0; R 13 is -CH(R 33 )-, where R 33 is COOH; and R 14 is nil.
  • lactam moieties include the pyrazolidinones of the representative formula: wherein, referring to formula (I), bond "a” is a single bond; bond “b” is a double bond; R 12 is -CH 2 -R 28- , where R 28 is -N-; R 13 is -C(R 33 )-, where R 33 is COOH; and R 14 is W-C"'-R 37 -, where R 37 is methylene, and W is C(R 38 ).
  • lactam moieties include the gamma-lactams of the representative formula: wherein, referring to formula (II), bond "a” is a single bond; bond "b” is nil; R 12 is -CH 2 -R 28- , where R 28 is -C(R 8a ) and R 8a is hydrogen; R 13 is -SO 3 H, -PO(OR 34 )OH, -C(O)NHSO 2 N(R 34 )(R 35 ), -OSO 3 H, -CH(R 35 )COOH, or -OCH(R 34 )COOH; and R 14 is nil.
  • lactam-containing moieties include isocephems, iso-oxacephems, oxacephems, carbacephems, penicillins, penems, carbapenems, and monocyclic beta-lactams. More preferred are penems, carbapenems and monocyclic beta-lactams. Particularly preferred lactam-containing moieties for compounds made by this invention are penems.
  • R 10 in formula (II), is any radical that may be substituted at the active stereoisomeric position of the carbon adjacent to the lactam carbonyl of an antimicrobially-active lactam.
  • antimicrobially-active lactam refers to a lactam-containing compound, without a quinolonyl substituent moiety, which has antimicrobial activity.
  • This "active" position is beta (i.e., 7-beta) for oxacephems and carbacephems (for example).
  • the active position is alpha for penems, carbapenems, clavems and clavams.
  • R 10 groups will be apparent to one of ordinary skill in the art. Many such R 10 groups are known in the art, as described in the following documents: Cephalosporins and Penicillins: Chemistry and Biology (E. Flynn, editor, 1972); Chemistry and Biology of b-Lactam Antibiotics (R. Morin et al., editors, 1987); "The Cephalosporin Antibiotics: Seminar-in-Print", 34 Drugs (Supp. 2) 1 (J. Williams, editor, 1987); New Beta-Lactam Antibiotics: A Review from Chemistry of Clinical Efficacy of the New Cephalosporins (H. Neu, editor, 1982); M.
  • R 10 is preferably lower alkyl, or hydroxy-substituted lower alkyl.
  • Particularly preferred R 10 groups include hydrogen, hydroxymethyl, ethyl, [1(R)-hydroxyethyl], [1(R)-[(hydroxysulfonyl)oxyethyl]], and [1-methyl-1-hydroxyethyl].
  • preferred R 10 groups are amides, such as: acetylamino, preferably substituted with aryl, heteroaryl, aryloxy, heteroarylthio and lower alkylthio substituents; arylglycylamino, preferably N-substituted with heteroarylcarbonyl and cycloheteroalkylcarbonyl substituents; arylcarbonylamino; heteroarylcarbonylamino; and lower alkoxyiminoacetylamino, preferably substituted with aryl and heteroaryl substituents.
  • Suitable R 11 groups are among those well-known in the art, including those defined in the following documents. W. Durckheimer et al., "Recent Developments in the Field of Beta-Lactam Antibiotics", 24 Angew. Chem. Int. Ed. Engl. 180 (1985); G. Rolinson, "Beta-Lactam Antibiotics", 17 J. Antimicrobial Chemotherapy 5 (1986); and EP-A-0 187,456, Jung, published July 16, 1986.
  • Preferred R 11 groups include hydrogen, methoxy, ethoxy, propoxy, thiomethyl, halogen, cyano, formyl and formylamino. Particularly preferred R 11 groups include hydrogen, methoxy, halogen, and formylamino.
  • Groups A 1 , A 2 , A 3 , R 1 , R 3 , and R 4 of formula I form a moiety (herein, "quinolone moiety") present in any of a variety of quinolone, naphthyridine or related heterocyclic compounds known in the art to have antimicrobial activity.
  • Such heterocyclic moieties are well known in the art, as described in the following articles: J. Wolfson et al., "The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro", 28 Antimicrobial Agents and Chemotherapy 581 (1985); and T. Rosen et al., 31 J. Med Chem. 1586 (1988); T. Rosen et al., 31 J.
  • Preferred quinolone moieties include those where A 1 is C(R 7 ), A 2 is C(R 2 ), and A 3 is C(R 5 ) (i.e., quinolones); A 1 is nitrogen, A2 is C(R 2 ), and A 3 is C(R 5 ) (i.e., naphthyridines); A 1 is C(R 7 ), A 2 is C(R 2 ) , and A 3 is nitrogen (i.e., cinnoline acid derivatives); and where A 1 is nitrogen, A 2 is nitrogen, and A 3 is C(R 5 ) (i.e., pyridopyrimidine derivatives).
  • More preferred quinolone moieties are those where A 1 is C(R 7 ), A 2 is C(R 2 ), and A 3 is C(R 5 ) (i.e., quinolones); and where A 1 is nitrogen, A 2 is C(R 2 ), and A 3 is C(R 5 ) (i.e., naphthyridines).
  • Particularly preferred quinolone moieties are where A 1 is C(R 7 ), A 2 is C(R 2 ), and A 3 is C(R 5 ) (i.e., quinolones).
  • R 1 is preferably alkyl, aryl, cycloalkyl and alkylamino. More preferably, R 1 is ethyl, 2-fluoroethyl, 2-hydroxyethyl, t-butyl, 4-fluorophenyl, 2,4-difluorophenyl, methylamino and cyclopropyl. Cyclopropyl is a particularly preferred R 1 group. Preferred quinolone moieties also include those where A 1 is C(R 7 ) and R 1 and R 7 together comprise a 6-membered heterocyclic ring containing an oxygen or sulfur atom.
  • R 2 is preferably hydrogen or halo. More preferably R 2 is chlorine or fluorine. Fluorine is a particularly preferred R 2 group.
  • Preferred R 3 groups include nitrogen-containing heterocyclic rings. Particularly preferred are nitrogen-containing heterocyclic rings having from 5 to 8 members.
  • the heterocyclic ring may contain additional heteroatoms, such as oxygen, sulfur, or nitrogen, preferably nitrogen.
  • Such heterocyclic groups are described in US-A-4,599,334, Petersen et al., issued July 8, 1986; and US-A-4,670,444, Grohe et al., issued June 2, 1987.
  • R 3 groups include unsubstituted or substituted pyridine, piperidine, morpholine, diazabicyclo[3.1.1]heptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazabicyclo[2.2.2] octane, thiazolidine, imidazolidine, pyrrole and thiamorpholine, as well as the following particularly preferred R 3 groups include piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N,N-dimethylaminomethylpyrrolidine, N-methylaminomethylpyrrolidine, N-ethylaminomethylpyrrolidine, pyridine, N-methylpiperazine, and 3,5-dimethylpiperazine.
  • the specific physical, chemical, and pharmacological properties of the quinolonyl lactams of this invention may depend upon the particular combination of the integral lactam-containing moiety, quinolone moiety and linking moiety comprising the compound.
  • selection of particular integral moieties may affect the relative susceptibility of the quinolonyl lactam to bacterial resistance mechanisms (e.g., beta-lactamase activity).
  • Preferred quinolone compounds herein are:
  • Preferred lactam compounds herein are:
  • lactam moieties are described in the following documents: EP-A-0 366,189, White and Demuth, published May 2, 1990; EP-A-0 335, 297, Albrecht et al., published October 4, 1989; and U.S. Patent Application Serial No. 07/511,483, Demuth and White, filed April 18, 1990.
  • the process of this invention additionally comprises:
  • R 10 substituent or the lactam compound may need to be protected or blocked in order to prevent undesired competing side reactions from occurring during the coupling step.
  • Protecting groups for hydroxyl substituents include ethers, esters, and carbonates; and protecting groups for amino substituents include carbamates, and amides. If various protecting groups are employed, then an appropriate deprotecting step, that will not decompose the coupled conjugate, may be required to obtain antibacterially active products. Chemistry useful in the protecting and deprotecting steps are well known in the chemical literature.
  • a silylated quinolone compound is used in the coupling step, wherein R 44 of the quinolone compound is Si(R 45 ) 3 , and R 45 is lower alkyl.
  • R 45 is methyl or ethyl.
  • the R 45 groups may be independently selected, such that the Si(R 45 ) 3 moiety need not contain three identical R 45 substituents.
  • silylating reagents Any of a number of silylating reagents known in the art may be used to form the silylated quinolone compound, by reacting the silylating agent with a quinolone compound wherein R 44 is hydrogen.
  • silylating reagents include, for example, chlorotrimethylsilane; N-methyl-N-trimethylsilyl-trifluoroacetamide; N,N-bis(trimethylsilyl)urea; 1-trimethylsilylimidazole; bis(trimethylsilyl)trifluoroacetamide; and N,O-bis(trimethylsilyl)acetamide.
  • silylating agent to form a silylated quinolone compound may also yield a silyl ester of R 4 carboxylate of the quinolone, as a protecting group. This ester can then be removed, using well-known deprotection chemistry.
  • the reacting step and coupling step are carried out in solution, using any of a variety of suitable solvents.
  • suitable solvents include, for example: halocarbon solvents, such as methylene chloride, chloroform, and dichloroethane; ethers, such as diethyl ether and tetrahydrofuran (THF); aromatic solvents, such as benzene and toluene; and mixtures thereof.
  • halocarbon solvents such as methylene chloride, chloroform, and dichloroethane
  • ethers such as diethyl ether and tetrahydrofuran (THF)
  • aromatic solvents such as benzene and toluene
  • the coupling step comprises adding a solution containing the quinolone compound to a solution containing the intermediate compound.
  • the reacting step and coupling step are conducted at low temperatures, from about -80° C to about -40° C.
  • reagents are mixed in the reaction step and coupling step so as to allow control of the temperature within these ranges.
  • a 3-neck, 1 L flask is fitted with a low temperature thermometer, overhead stirrer and a 500 mL dropping funnel.
  • the apparatus is dried and then cooled to approximately -78° C under nitrogen with a dry ice/acetone bath.
  • Phosgene 60 mL, 20% in toluene
  • Dichloromethane is then rinsed through the dropping funnel into the flask.
  • N-methyl-N-trimethylsilyl-trifluoroacetamide (56 mL) is added to a suspension of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid (33.2 gram) in 250 mL dichloromethane at room temperature.
  • the resulting solution is transferred to the dropping funnel on the 1 L flask via cannula and is added to the reaction mixture at such a rate so as to maintain the reaction temperature between -75° C and -70° C over approximately 1.5 hour.
  • reaction mixture is stirred for approximately 15 minutes, the cooling bath is removed and 50 mL of water is added, allowing the solution to warm to approximately -10° C. A second aliquot of water (50 mL) is added and the mixture is further warmed to 10° C.
  • reaction is stirred 1 hour at -35° C to -45° C, then cooled to -78° C.
  • the solid is ground by mortar and pestle with acetone and further triturated with acetone.
  • the solid is filtered and triturated with a 1:12 mixture of aqueous isopropanol.
  • the solid is filtered to yield 0.22 gram the title compound.
  • a 30 L reactor is fitted with a low temperature thermometer, overhead stirrer is charged with dichloromethane (6 L) and toluene (1.8 L) and cooled to -78° C (internal temperature). Phosgene gas is introduced keeping the temperature below approximately -60° C.
  • a 30 L reactor is charged with THF (5.3 L), tetrabutylammonium fluoride (3.22 L, 1 M in THF) and acetic acid (790 mL).
  • Solid product I (870 gram) is added at room temperature with overhead stirring and the resulting suspension is stirred under nitrogen for 20-24 hours. The reaction mixture becomes homogenous overnight.
  • Water (20 L) is added to the reactor, the resulting suspension stirred for one hour, and then the product is filtered.
  • the crude product is placed into the 30 L reactor, more water (20 L) is added, the suspension is stirred for 1 h, and then the product is refiltered, washed with THF (5 L), and then dried to give approximately 550 gram of product II.
  • a 30 L reactor equipped with an overhead stirrer is charged with product II (200 gram) and dichloromethane (12 L).
  • the flask is purged with nitrogen and tetrakis(triphenyl-phosphine)palladium(0) (18 g) is added.
  • the reaction mixture is cooled to -5° C and a solution of sodium 2-ethylhexanoate (103 g) in THF (6 L) is slowly added to the reaction vessel via a metering pump at such a rate that the internal temperature was maintained between -5° C to 0° C. Stirring of the reaction mixture is continued at - 5° C for another 1.5 hour after completion of addition.
  • the reaction mixture is then centrifuged, the supernatant decanted off, and the product washed with additional dichloromethane (6 L). Following centrifugation and decantation, the product is then washed with additional dichloromethane (6 L). This process of washing, centrifugation, and decantation is repeated twice more. Following the final decantation step, final drying of the product affords 180 grams of the title compound.

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Abstract

The present invention provides methods of making compounds of the structure (Q-L1)-L-(L2-B( wherein (I) Q is a quinolone moiety; (II) B is a beta-lactam moiety; (III) L, L1, and L2 together comprise a carbamate-containing linking moiety comprising the steps of: (1) Reacting a lactam compound of the formula B-L4-H with phosgene to form an intermediate compound of the formula B-L4-C(=O)-Cl, where L4 is oxygen; and (2) Coupling said intermediate compound with a quinolone compound of the formula Q-L3-R44; wherein L3 is nitrogen; R44 is hydrogen, Si(R45)3, or Sn(R45)3; and R45 is lower alkyl. Preferably, the process additionally comprises steps prior to the reacting and coupling steps where esters of the lactam and quinolone compounds are made. Also preferably, the coupling step comprises adding a solution containing the quinolone compound to a solution containing the intermediate compound. The process steps are also preferably performed at a temperature of from about -80 degrees C. to about 0 degrees C. Preferred antimicrobial compounds made by these processes are those where the beta-lactam moiety is a penem.

Description

  • This invention relates to processes for making antimicrobial compounds. The compounds made by this invention contain, as integral substituents, a quinolone moiety and a lactam-containing moiety.
  • The chemical and medical literature describes a myriad of compounds that are said to be antimicrobial, i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. In particular, antibacterials include a large variety of naturally-occurring (antibiotic), synthetic, or semi-synthetic compounds. They may be classified (for example) as the aminoglycosides, ansamacrolides, beta-lactams (including penicillins and cephalosporins), lincosaminides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines, and sulfonamides. Such antibacterials and other antimicrobials are described in Antibiotics, Chemotherapeutic and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition (1981).
  • Recently, a new class of highly potent, broad spectrum antimicrobials was discovered, combining beta-lactam moieties with quinolone moieties. These compounds have been referred to as "Quinolony Lactam Antimicrobials" (herein referred to as "QLAs)." Such compounds are described in EP-A-0 366,189, White and Demuth, published May 2, 1990; EP-A-0,366,193, Demuth and White, published May 2, 1990; EP-A-0 366,640, Demuth and White, published May 2, 1990; and EP-A-0, 366, 641, White and Demuth, published May 2, 1990. Other such compounds are described in Australian Patent Publication 87/75009, Albrecht et al., published January 7, 1988; Australian Patent Publication 88/27554, published June 6, 1989; EP-A-0 335, 297, Albrecht et al., published October 4, 1989; and Albrecht et al., "Dual-Action Cephalosporins: Cephalosporin 3'-Quinolone Carbamates", 34 J. Medicinal Chemistry 2857 (1991).
  • Manufacture of QLAs generally involves synthesis of suitably protected substituent beta-lactam and quinolone moieties, a linking process, and appropriate de-protection steps. The specific linking process depends, of course, on the specific lactam and quinolone substituent moieties used, as well as the type of linkage desired. Several such linking processes have been described in the literature. EP-A-0,451,764 discloses carbapenem compounds and processes for their preparation. In particular, a reaction between phosgene and carbapenem alcohol at 0°C to room temperature is disclosed. However, the yields of these processes are often low, particularly for the preparation of QLAs having a penem substituent moiety.
  • It has now been discovered that certain linking processes using phosgene are useful in making QLAs, particularly those having a penem substituent moiety. Such processes allow efficient synthesis of QLAs, with high yields.
  • According to the present invention there is provided a process for making an antimicrobial compound of the formula :

            [Q - L1] - L - [L2 - B]

    wherein
    • (I) Q is a structure according to Formula (I)
      Figure imgb0001
       wherein
      • (A)
        • (1) A1 is N or C(R7); where
          • (i) R7 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R8)(R9), and
          • (ii) R8 and R9 are, independently, R8a where R8a is hydrogen, alkyl, alkenyl, carbocyclic ring, or heterocyclic ring; or R8 and R9 together comprise a heterocyclic ring including the nitrogen to which they are bonded;
        • (2) A2 is N or C(R2); where R2 is hydrogen or halogen;
        • (3) A3 is N or C(R5); where R5 is hydrogen;
        • (4) R1 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R8)(R9);
        • (5) R3 is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring;
        • (6) R4 is hydroxy; and
        • (7) R6 is hydrogen, halogen, nitro or N(R8)(R9);
      • (B) except that
        • (1) when A1 is C(R7), R1 and R7 may together comprise a heterocyclic ring including N' and A1;
        • (2) when A2 is C(R2), R2 and R3 may together comprise -O-(CH2)n-O-, where n is an integer from 1 to 4;
        • (3) when A3 is C(R5), R4 and R5 may together comprise a heterocyclic ring including the carbon atoms to which R4 and R5 are bonded and the carbon atom of Formula (I) to which said carbon atoms are bonded; and
        • (4) when A3 is C(R5), R1 and R5 may together comprise a heterocyclic ring including N' and the adjacent carbon to which R5 is bonded;
      • (C) and except that one of R1, R6, or R3 must be nil;
    • (II) B is a structure according to Formula (II):
      Figure imgb0002
       wherein
      • (A) R10 is hydrogen, halogen, alkyl, alkenyl, heteroalkyl, a carbocyclic ring, a heterocyclic ring, R8a-0-, R8aCH=N-, (R8)(R9)N-, R17-C(=CHR20)-C(=O)NH-, R17-C(=NO-R19)-C(=O)NH-, or R18-(CH2)m-C(=O)NH-; where
        • (1) m is an integer from 0 to 9;
        • (2) R17 is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring;
        • (3) R18 is R17, -Y1, or -CH(Y2)(R17);
        • (4) R19 is R17, arylalkyl, heteroaryl alkyl, -C(R22)(R23)COOH, -C(=O)O-R17, or -C(=O)NH-R17, where R22 and R23 are, independently, R17 or together comprise a carbocyclic ring or a heterocyclic ring including the carbon atom to which R22 and R23 are bonded;
        • (5) R20 is R19, halogen, -Y1, or -CH(Y2)(R17);
        • (6) Y1 is -C(=O)OR21, -C(=O)R21, -N(R24)R21, -S(O)pR29, or -OR29; and Y2 is Y1 or -OH, -SH, or -SO3H;
          • (a) p is an integer from 0 to 2;
          • (b) R24 is hydrogen; alkyl; alkenyl; heteroalkyl; heteroalkenyl; a carbocyclic ring; a heterocyclic ring; -SO3H; -C(=0)R25; or, when R18 is -CH(N(R24)R21)(R17), R24 may comprise a moiety bonded to R21 to form a heterocyclic ring; and
          • (c) R25 is R17, NH(R17), N(R17)(R26), O(R26), or S(R26); where R26 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or when R25 is N(R17)(R26), R26 may be a moiety bonded to R17 to form a heterocyclic ring; and
        • (7) R21 is R29 or hydrogen; where R29 is alkyl; alkenyl; arylalkyl; heteroalkyl; heteroalkenyl; heteroarylalkyl; a carbocyclic ring; a heterocyclic ring; or, when Y is N(R24)R21 and R21 is R29, R21 and R24 may together comprise a heterocyclic ring including the nitrogen atom to which R24 is bonded;
      • (B) R11 is hydrogen, halogen, alkoxy, or R27C(=O)NH-, where R27 is hydrogen or alkyl;
      • (C) bond "a" is a single bond or is nil; and bond "b" is a single bond, a double bond, or is nil; except bond "a" and bond "b" are not both nil;
      • (D) R12 is
        Figure imgb0003
         where R28 is
        Figure imgb0004
         and R28 is directly bonded to N" in Formula (II) to form a 5-membered ring; except, if bond "a" is nil, then R12 is
        • (1) -C(R8a)(X1)-, where
          • (i) X1 is -R21; -OR30; -S(O)rR30, where r is an integer from 0 to 2; -0C(=O)R30; or N(R30)R31; and
          • (ii) R30 and R31 are, independently, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituents; or R30 and R31 together comprise a heterocyclic ring including the nitrogen atom to which R30 and R31 are bonded; or
        • (2) -CH2-R32-; where R32 is
          Figure imgb0005
           -O-, or
          Figure imgb0006
           and R32 is directly bonded to N" in Formula (II) to form a 5-membered ring;
      • (E)
        • (1) if bond "b" is a single bond, R13 is -CH(R33)-; or, -C(O)NHSO2-, if bond "a" is nil; or
          Figure imgb0007
           if R14 contains a R36 moiety; where R33 is hydrogen or COOH, and C* is linked to R36 to form a 3-membered ring;
        • (2) if bond "b" is a double bond, R13 is -C(R33)=; or
        • (3) if bond "b" is nil, R13 is hydrogen, -SO3H, -PO(OR34)OH, -C(O)NHSO2N(R34)(R35), -OSO3H, -CH(R35)COOH, or -OCH(R34)COOH; where R34 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R35 is hydrogen, alkyl, alkenyl, or -NHR8a; or, if R13 is -C(O)NHSO2N(R34)(R35), R34 and R35 may together comprise a heterocyclic ring including the nitrogen to which R34 and R35 are bonded; and
      • (F)
        • (1) if bond "a" or bond "b" is nil, then R14 is nil;
        • (2) if bond "a" and "b" are single bonds, R14 is
          Figure imgb0008
           or
        • (3) if bond "a" is a single bond and bond "b" is a double bond, R14 is
          Figure imgb0009
          Figure imgb0010
           where
          • (a) W is O; S(O)s, where s is an integer from 0 to 2; or C(R8a)(R38), where R38 is hydrogen, alkyl or alkoxy;
          • (b) W' is O; or C(R8a)(R38);
          • (c) R36 hydrogen; alkyl; alkenyl; -COOH; or, if R13 is
            Figure imgb0011
             R36 may be linked to C* to form a 3-membered carbocyclic ring;
          • (d) R37 and is nil, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and
          • (e) C"' is directly bonded to R13 to form a 5- or 6-membered ring; and
    • (III)
      • (A) L is -C(=O)-, and is bonded to L3 and L4
      • (B) L1 is L3 or R15L3; where
        • (1) L3 is NH;
        • (2) R15 is alkyl, alkenyl, heteroalkyl, a heterocyclic ring, a carbocyclic ring, or R15 together with L3 is a heteroalkyl or a heterocyclic ring; and
        • (3) L1 is bonded to Q at the point of attachment of R1, R6 or R3, whichever is nil;
      • (C) L2 is L4, -X2 t-R39-L4, or -X3t-R39-L4; where
        • (1) L4 is oxygen;
        • (2) X2 is oxygen, or S(O)v, where v is 0, 1, or 2;
        • (3) X3 is nitrogen; N(R40); N+(R41)(R42); or R43-N(R41); and is linked to R14 by a single or double bond; or, if R14 is nil, X3 is linked to B by a single or double bond; where
          • (a) R40 is R8a; -OR8a; or -C(=O)R8a;
          • (b) R41 and R42 are, independently, hydrogen; alkyl; alkenyl; carbocyclic rings; heterocyclic rings;
          • (c) R43 is N(R41), oxygen or sulfur;
        • (4) t is 0 or 1;
        • (5) R39 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring; and
        • (6)
          • (a) if bond "a" or bond"b" is nil, then L2 is bonded directly to R12 or R13; or
          • (b) if bond "a" and bond "b" are not nil, then L2 is bonded to R14;
      and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof;
    comprising the steps of:
    • (1) Reacting a lactam compound of the formula B-L2-H with phosgene to form an intermediate compound of the formula B-L2-C-(=O)-Cl; and
    • (2) Coupling said intermediate compound with a quinolone compound of the formula Q-L1-R44; wherein R44 is hydrogen, Si(R45)3, or Sn(R45)3; and R45 is lower alkyl,
    and additionally comprising
    • (a) a step, prior to said reacting step, wherein an ester of said lactam compound is formed;
    • (b) a step, prior to said coupling step, wherein an ester of said quinolone compound is formed; and
    • (c) deprotection steps, after said coupling step, wherein said esters are removed,
    wherein said reacting step and said coupling step are performed at a temperature of from about -80°C to about -40°C. Preferred antimicrobial compounds made by these processes are those where R14 is
    Figure imgb0012
     more preferably wherein W is S(O)s.
  • The present invention encompasses methods for making certain QLAs. These compounds are useful for treating infectious disorders in humans or other animal subjects. Thus, the compounds made by this invention must be pharmaceutically acceptable. As used herein, such a "pharmaceutically-acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.

            QLAs

  • The compounds ("QLAS") made by the methods of this invention encompass any of a variety of lactam moieties linked, by a linking moiety, to a quinolone moiety at the 1-, 5-, or 7-position of the quinolone. These compounds include those having the general formula

            [Q - L1] - L - [L2 - B]

    wherein Q, L', L, L2 and B are as defined hereinabove.
  • Preferred antimicrobial compounds made by the processes of this invention include those where R3 is nil and comprises a bond to L1, and those where R6 is nil and comprises a bond to L1.
    • Definitions and Usage of Terms: The following is a list of definitions for terms used herein.
  • "Heteroatom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.
  • "Alkyl" is a saturated hydrocarbon chain radical having from 1 to 8 carbon atoms, preferably from 1 to 4 carbon atoms. Preferred alkyl groups include (for example) methyl, ethyl, propyl, isopropyl, and butyl.
  • "Heteroalkyl" is a saturated chain radical having from 3 to 8 members comprising carbon atoms and one or two heteroatoms.
  • "Alkenyl" is a hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond.
  • "Carbocyclic ring" is a saturated, unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
  • "Cycloalkyl" is a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl.
  • "Heterocyclic ring" is a saturated, unsaturated or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
  • "Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl and naphthyl.
  • "Heteroaryl" is an aromatic heterocyclic ring radical. Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, quinolinyl, pyrimidinyl and tetrazolyl.
  • "Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl (i.e., -O-alkyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy.
  • "Alkylamino" is an amino radical having an alkyl substituent (i.e., -NH-alkyl).
  • "Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl and phenylethyl.
  • "Arylamino" is an amine radical substituted with an aryl group (i.e., -NH-aryl).
  • "Aryloxy" is an oxygen radical having a aryl substituent (i.e., -O-aryl).
  • "Acyl" or "carbonyl" is a radical formed by removal of the hydroxy from an carboxylic acid (i.e., R-C(=O)-). Preferred alkylacyl groups include (for example) acetyl, formyl, and propionyl.
  • "Acyloxy" is an oxygen radical having an acyl substituent (i.e., -O-acyl); for example,-O-C(=O)-alkyl.
  • "Acylamino" is an amino radical having an acyl substituent (i.e., -NH-acyl); for example, -NH-C(=O)-alkyl.
  • "Halo", "halogen", or "halide" is a chloro, bromo, fluoro or iodo atom radical. Chloro and fluoro are preferred halides.
  • Also, as referred to herein, a "lower" hydrocarbon moiety (e.g., "lower" alkyl) is a hydrocarbon chain comprised of from 1 to 6, preferably from 1 to 4, carbon atoms.
  • A "pharmaceutically-acceptable salt" is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium). Preferred anionic salts include the halides (such as chloride salts).
  • A "biohydrolyzable ester" is an ester of a QLA that does not essentially interfere with the antimicrobial activity of the compounds, or that are readily metabolized by a human or lower animal subject to yield an antimicrobially-active quinolonyl lactam. Such esters include those that do not interfere with the biological activity of quinolone antimicrobials or beta-lactam antimicrobials (cephems, for example). Many such esters are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987. Such esters-include lower alkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and alkyl acylamino alkyl esters (such as acetamidomethyl esters).
  • As defined above and as used herein, substituent groups may themselves be substituted. Such substitution may be with one or more substituents. Such substituents include (for example) those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979). Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
  • Also, as used in defining the structure of the compounds of this invention, a particular radical may be defined for use as a substituent in multiple locations. For example, the R8 substituent is defined as a potential substituent of R7, but is also incorporated into the definition of other substituents (such as R1, R6, and R10. As used herein, such a radical is independently selected each time it is used (e.g., R8 need not be alkyl in all occurrences in defining a given compound of this invention).
    • Lactam-containing moiety:
  • Groups R12, R13, and R14, together with bonds "a" and "b" of formula (I), form any of a variety of lactam-containing moieties known in the art to have antimicrobial activity. Such moieties wherein either bond "a" or bond "b" are nil (i.e., do not exist) are mono-cyclic; if both bonds exist, the structures are bi-cyclic. Preferably, bond "a" is a single bond and bond b" is a double bond.
  • Preferred lactam moieties include the oxacephems and carbacephems of the representative formula:
    Figure imgb0013
     wherein, referring to formula (II), bond "a" is a single bond; bond "b" is a double bond; R12 is -C(R8a)-, where R8a is hydrogen; R13 is -CH(R33), where R33 is COOH; and R14 is -W'-C(R8a)(R38)-C'"-R37, where R8a and R38 are hydrogen, R37 is methylene, and W' is 0 (for oxacephems) or C(R38) (for carbacephems).
  • Other preferred lactam moieties include the isocephems and iso-oxacephems of the representative formula:
    Figure imgb0014
     wherein, referring to formula II, bond "a" is a single bond; bond "b" is a double bond; R12 is -C(R8a) where R8a is hydrogen; R13 is -C(R33)-, where R33 is COOH; and R14 is -C(R8a)(R38)-W-C"'-R37 where R8a and R38 are each hydrogen, R37 is methylene, and W is S (for isocephems) or O (for iso-oxacephems).
  • Other preferred lactam-containing moieties include the penems, carbapenems and clavems, of the representative formula:
    Figure imgb0015
     wherein, referring to formula (II), bond "a" is a single bond; bond "b" is a double bond; R12 is -C(R8a), where R8a is hydrogen; R13 is -C(R33)-, where R33 is COOH; and R14 is -W-C"'-R37, where R37 is methylene, and W is S (for penems), C(R38) (for carbapenems), or O (for clavems). Such lactam moieties are described in the following articles: R. Wise, "In Vitro and Pharmacokinetic Properties of the Carbapenems", 30 Antimicrobial Agents and Chemotherapy 343 (1986); and S. McCombie et al., "Synthesis and In Vitro Activity of the Penem Antibiotics", 8 Medicinal Research Reviews 393 (1988).
  • Other preferred lactam-containing moieties of this invention include the penicillins of the representative formula:
    Figure imgb0016
     wherein, referring to formula II, bond "a" is a single bond, bond "b" is a single bond; R12 is -C(R8a)-, where R8a is hydrogen; R13 is -CH(R33)- where R33 is COOH; and R14, is -W-C"'(R36)-R37- where R36 is methyl, R37 is methylene, and W is S.
  • Other preferred lactam-containing moieties include the monocyclic beta-lactams, of the representative formula:
    Figure imgb0017
     wherein, referring to formula (II), bond "a" is a single bond; bond "b" is-nil; R12 is -C(R8a)-, where R8a is hydrogen; R14 is nil; and R13 is -SO3H (for a monobactam), -PO(OR34)OH (for a monophospham); -C(O)NHSO2N(R34)(R35) (for a monocarbam), -OSO3H (for a monosulfactam), -CH(R35)COOH (for nocardicins), or -OCH(R34)COOH. Such lactam moieties are described in C. Cimarusti et al., "Monocyclic 8-lactam Antibiotics", 4 Medicinal Research Reviews 1 (1984).
  • Other preferred lactam moieties include the monocyclic beta-lactams of the representative formula:
    Figure imgb0018
     wherein referring to formula II, bond "a" is nil, bond "b" is a single bond; R12 is -C(R8a)(R29)- where both R8a and R29 are hydrogen; and R14 is nil.
  • Other preferred lactam moieties include the clavams of the representative formula:
    Figure imgb0019
     wherein, referring to formula (II), bond "a" is a single bond; bond "b" is a single bond; R12 is s -C(R8a)-, where R8a is hydrogen; R13 is -CH(R33)-, where R33 is COOH; and R14 is W-C"'=C-(R8a)-R37, where R8a is hydrogen and R37 is methylene, and W is O.
  • Other preferred lactam moieties include the 2,3-methylenopenams and -carbapenams of the representative formula:
    Figure imgb0020
     wherein, referring to formula (II), bond "a" is a single bond; bond "b" is a single bond; R12 is -C(R8a)-, where R8a is hydrogen; R13 is -C*(R33), where R33 is COOH; and R14 is W-C"'(R36)-R37, where R37 is nil, R36 is linked to C* to form a 3-membered carbocyclic ring, and W is C(R38) or sulfur.
  • Lactam moieties of this invention also include the lactivicin analogs of the representative formula:
    Figure imgb0021
     wherein, referring to formula (II), bond "a" is nil; bond "b" is a single bond; R12 is -CH2-R32, where R32 is 0; R13 is -CH(R33)-, where R33 is COOH; and R14 is nil.
  • Other lactam moieties include the pyrazolidinones of the representative formula:
    Figure imgb0022
     wherein, referring to formula (I), bond "a" is a single bond; bond "b" is a double bond; R12 is -CH2-R28-, where R28 is -N-; R13 is -C(R33)-, where R33 is COOH; and R14 is W-C"'-R37-, where R37 is methylene, and W is C(R38).
  • Other lactam moieties include the gamma-lactams of the representative formula:
    Figure imgb0023
     wherein, referring to formula (II), bond "a" is a single bond; bond "b" is nil; R12 is -CH2-R28-, where R28 is -C(R8a) and R8a is hydrogen; R13 is -SO3H, -PO(OR34)OH, -C(O)NHSO2N(R34)(R35), -OSO3H, -CH(R35)COOH, or -OCH(R34)COOH; and R14 is nil.
  • Preferred lactam-containing moieties include isocephems, iso-oxacephems, oxacephems, carbacephems, penicillins, penems, carbapenems, and monocyclic beta-lactams. More preferred are penems, carbapenems and monocyclic beta-lactams. Particularly preferred lactam-containing moieties for compounds made by this invention are penems.
  • R10, in formula (II), is any radical that may be substituted at the active stereoisomeric position of the carbon adjacent to the lactam carbonyl of an antimicrobially-active lactam. (As used herein, the term "antimicrobially-active lactam" refers to a lactam-containing compound, without a quinolonyl substituent moiety, which has antimicrobial activity.) This "active" position is beta (i.e., 7-beta) for oxacephems and carbacephems (for example). The active position is alpha for penems, carbapenems, clavems and clavams.
  • Appropriate R10 groups will be apparent to one of ordinary skill in the art. Many such R10 groups are known in the art, as described in the following documents: Cephalosporins and Penicillins: Chemistry and Biology (E. Flynn, editor, 1972); Chemistry and Biology of b-Lactam Antibiotics (R. Morin et al., editors, 1987); "The Cephalosporin Antibiotics: Seminar-in-Print", 34 Drugs (Supp. 2) 1 (J. Williams, editor, 1987); New Beta-Lactam Antibiotics: A Review from Chemistry of Clinical Efficacy of the New Cephalosporins (H. Neu, editor, 1982); M. Sassiver et al., in Structure Activity Relationships among the Semi-synthetic Antibiotics (D. Perlman, editor, 1977). W. Durckheimer et al., "Recent Developments in the Field of Beta-Lactam Antibiotics", 24 Angew. Chem. Int. Ed. Engl. 180 (1985); G. Rolinson, "Beta-Lactam Antibiotics", 17 J. Antimicrobial Chemotherapy 5 (1986); EP-A-0 187,456, Jung, published July 16, 1986; and World Patent Publication 87/05297, Johnston et al., published September 11, 1987.
  • For penems, carbapenems, clavems and clavams, R10 is preferably lower alkyl, or hydroxy-substituted lower alkyl. Particularly preferred R10 groups include hydrogen, hydroxymethyl, ethyl, [1(R)-hydroxyethyl], [1(R)-[(hydroxysulfonyl)oxyethyl]], and [1-methyl-1-hydroxyethyl].
  • Except for penems, carbapenems, clavems and clavams, preferred R10 groups are amides, such as: acetylamino, preferably substituted with aryl, heteroaryl, aryloxy, heteroarylthio and lower alkylthio substituents; arylglycylamino, preferably N-substituted with heteroarylcarbonyl and cycloheteroalkylcarbonyl substituents; arylcarbonylamino; heteroarylcarbonylamino; and lower alkoxyiminoacetylamino, preferably substituted with aryl and heteroaryl substituents. Particularly preferred R10 groups include amides of the general formula R18-(CH2)m-C(=O)NH- and R18 is R17. Examples of such preferred R10 groups include:
    • [(2-amino-5-halo-4-thiazolyl)acetyl)amino;
    • [(4-aminopyridin-2-yl)acetyl]amino;
    • [[(3,5-dlchloro-4-oxo-1(4H)-pyridinyl)acetyl]amino];
    • [[[2-(aminomethyl)phenyl]acetyl]amino];
    • [(1H-tetrazol-1-ylacetyl)amino];
    • [(cyanoacetyl)amino];
    • [(2-thienylacetyl)amino];
    • [[(2-amino-4-thiazoyl)acetyl]amino]; and
    • sydnone, 3-[-2-amino]-2-oxoethyl.
  • When R10 is R18-(CH2)m-C(C=O)NH-, and R18 is -Y1, preferred R10 groups include the following:
    • [sulfamoylphenylacetyl]amino;
    • [[(4-pyridinylthio)acetyl]amino];
    • [[[(cyanomethyl)thio]acetyl]amino];
    • (S)-[[[(2-amino-2-carboxyethyl)thio]acetyl]amino];
    • [[[(trifluoromethyl)thio]acetyl]amino]; and
    • (E)-[[[(2-aminocarbonyl-2-fluoroethenyl)thio]acetyl]amino].
  • When R10 is R18-(CH2)m-C(=O)NH-, and R18 is -CH(Y2)(R17), preferred R10 groups include the following:
    • [carboxyphenylacetyl]amino;
    • [(phenoxycarbonyl)phenylacetyl]amino;
    • [4-methyl-2,3-dioxo-1-piperazinecarbonyl-D-phenylglycyl]amino;
    • [[[3-(2-furylmethyleneamino)-2-oxo-1-imidazolidinyl]carbonyl]amino]phenyl]acetyl]amino;
    • (R)-[(aminophenylacetyl)amino];
    • (R)-[[amino(4-hydroxyphenyl)acetyl]amino];
    • (R)-[(amino-1,4-cyclohexadien-1-ylacetyl)amino];
    • [(hydroxyphenylacetyl)amino];
    • (R)-[[[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-(4-hydroxyphenyl)acetyl]amino];
    • (R)-[[[[(5-carboxy-1H-imidazol-4-yl)carbonyl]amino]phenylacetyl]amino];
    • (R)-[[[[(4-hydroxy-6-methyl-3-pyridinyl)carbonyl]amino](4-hydroxyphenyl)acetyl]amino];
    • (R)-[(phenylsulfoacetyl)amino];
    • (2R,3S)-[[2-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]-3-hydroxy-1-oxobutyl]amino];
    • [[carboxy(4-hydroxyphenyl)acetyl]amino];
    • (R)-[[amino[3-[(ethylsulfonyl)amino]phenyl]acetyl]amino];
    • (R)-[[amino(benzo[b]thien-3-yl)acetyl]amino];
    • (R)-[[amino(2-naphthyl)acetyl]amino];
    • (R)-[[amino(2-amino-4-thiazolyl)acetyl]amino];
    • [[[[(6,7-dihydroxy-4-oxo-4H-1-benzopyran-3-yl)carbonyl]amino](4-hydroxyphenyl)acetyl]amino];
    • (R,R)-[[2-[4-[2-amino-2-carboxyethyloxycarbonyl]aminophenyl]-2-hydroxyacetyl]amino]; and
    • (S)-[[(5-hydroxy-4-oxo-1(4H)-pyridin-2-yl)carbonylamino(2-amino-4-thiazolyl)acetyl]amino].
  • Another preferred R10 group is R17-C(=CHR20)-C(=O)NH-. Another class of preferred R10 groups (for lactam-containing moieties other than penems, carbapenems, clavems and clavams) include those of the formula:

            R17-C(=NO-R19)-C(=O)NH-.

    Examples of this preferred class of R10 groups include:
    • 2-phenyl-2-hydroxyiminoacetyl;
    • 2-thienyl-2-methoxyiminoacetyl; and
    • 2-[4-(gamma-D-glutamyloxy)phenyl]-2-hydroxyiminoacetyl. (Z)[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino];
    • [[(2-furanyl(methoxyimino)acetyl]amino];
    • (Z)-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methyl)ethoxyimino]acetyl]amino];
    • (Z)-[[(2-amino-4-thiazolyl)(1-carboxymethoxyimino)acetyl]amino];
    • [[(2-amino-4-thiazolyl)[(1H-imidazol-4-ylmethoxy)imino]acetyl]amino];
    • (Z)-[[(2-amino-4-thiazolyl-3-oxide)(methoxyimino)acetyl]amino]; and
    • (S,Z)-[[(2-amino-4-thiazolyl)[carboxy(3,4-dihydroxyphenyl)methoxyimino]acetyl]amino].
  • Suitable R11 groups are among those well-known in the art, including those defined in the following documents. W. Durckheimer et al., "Recent Developments in the Field of Beta-Lactam Antibiotics", 24 Angew. Chem. Int. Ed. Engl. 180 (1985); G. Rolinson, "Beta-Lactam Antibiotics", 17 J. Antimicrobial Chemotherapy 5 (1986); and EP-A-0 187,456, Jung, published July 16, 1986. Preferred R11 groups include hydrogen, methoxy, ethoxy, propoxy, thiomethyl, halogen, cyano, formyl and formylamino. Particularly preferred R11 groups include hydrogen, methoxy, halogen, and formylamino.
    • Quinolone Moieties:
  • Groups A1, A2, A3, R1, R3, and R4 of formula I form a moiety (herein, "quinolone moiety") present in any of a variety of quinolone, naphthyridine or related heterocyclic compounds known in the art to have antimicrobial activity. Such heterocyclic moieties are well known in the art, as described in the following articles: J. Wolfson et al., "The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro", 28 Antimicrobial Agents and Chemotherapy 581 (1985); and T. Rosen et al., 31 J. Med Chem. 1586 (1988); T. Rosen et al., 31 J. Med. Chem. 1598 (1988); G. Klopman et al., 31 Antimicrob. Agents Chemother. 1831 (1987); 31:1831-1840; J. P. Sanchez et al., 31 J. Med. Chem. 983 (1988); J. M. Domagala et al., 31 J. Med. Chem. 991 (1988); M. P. Wentland et al., in 20 Ann. Rep. Med. Chem. 145 (D. M. Baily, editor, 1986); J. B. Cornett et al., in 21 Ann. Rep. Med. Chem. 139 (D. M. Bailey, editor, 1986); P. 8. Fernandes et al., in 22 Ann. Rep. Med. Chem. 117 (D. M. Bailey, editor, 1987); R. Albrecht, 21 Prop. Drug Research 9 (1977); and P. B. Fernandes et al., in 23 Ann. Rep. Med. Chem. (R. C. Allen, editor, 1987).
  • Preferred quinolone moieties include those where A1 is C(R7), A2 is C(R2), and A3 is C(R5) (i.e., quinolones); A1 is nitrogen, A2 is C(R2), and A3 is C(R5) (i.e., naphthyridines); A1 is C(R7), A2 is C(R2 ), and A3 is nitrogen (i.e., cinnoline acid derivatives); and where A1 is nitrogen, A2 is nitrogen, and A3 is C(R5) (i.e., pyridopyrimidine derivatives). More preferred quinolone moieties are those where A1 is C(R7), A2 is C(R2), and A3 is C(R5) (i.e., quinolones); and where A1 is nitrogen, A2 is C(R2), and A3 is C(R5) (i.e., naphthyridines). Particularly preferred quinolone moieties are where A1 is C(R7), A2 is C(R2), and A3 is C(R5) (i.e., quinolones).
  • R1 is preferably alkyl, aryl, cycloalkyl and alkylamino. More preferably, R1 is ethyl, 2-fluoroethyl, 2-hydroxyethyl, t-butyl, 4-fluorophenyl, 2,4-difluorophenyl, methylamino and cyclopropyl. Cyclopropyl is a particularly preferred R1 group. Preferred quinolone moieties also include those where A1 is C(R7) and R1 and R7 together comprise a 6-membered heterocyclic ring containing an oxygen or sulfur atom.
  • R2 is preferably hydrogen or halo. More preferably R2 is chlorine or fluorine. Fluorine is a particularly preferred R2 group.
  • Preferred R3 groups include nitrogen-containing heterocyclic rings. Particularly preferred are nitrogen-containing heterocyclic rings having from 5 to 8 members. The heterocyclic ring may contain additional heteroatoms, such as oxygen, sulfur, or nitrogen, preferably nitrogen. Such heterocyclic groups are described in US-A-4,599,334, Petersen et al., issued July 8, 1986; and US-A-4,670,444, Grohe et al., issued June 2, 1987. Preferred R3 groups include unsubstituted or substituted pyridine, piperidine, morpholine, diazabicyclo[3.1.1]heptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazabicyclo[2.2.2] octane, thiazolidine, imidazolidine, pyrrole and thiamorpholine, as well as the following particularly preferred R3 groups include piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N,N-dimethylaminomethylpyrrolidine, N-methylaminomethylpyrrolidine, N-ethylaminomethylpyrrolidine, pyridine, N-methylpiperazine, and 3,5-dimethylpiperazine.
  • The specific physical, chemical, and pharmacological properties of the quinolonyl lactams of this invention may depend upon the particular combination of the integral lactam-containing moiety, quinolone moiety and linking moiety comprising the compound. For example, selection of particular integral moieties may affect the relative susceptibility of the quinolonyl lactam to bacterial resistance mechanisms (e.g., beta-lactamase activity).
  • Preferred quinolone compounds herein are:
    • 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid;
    • 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid allyl ester;
    • 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid diphenylmethyl ester;
    • 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid t-butyl ester;
    • 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid 2,2,2-trichloroethyl ester;
    • 7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro -4-oxo-quinoline-3-carboxylic acid;
    • 7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro -4-oxo-quinoline-3-carboxylic acid allyl ester;
    • 5-Amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4 -dihydro-4-oxo-quinoline-3-carboxylic acid allyl ester;
    • 5-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-piperazinyl)-4-oxo-quinoline-3-carboxylic acid;
    • 7-(3-Amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid allyl ester; or
    • 7-[3-(t-Butyloxycarbonyl)amino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-hydrazino-4-oxo-quinoline-3-carboxylic acid allyl ester.
  • Preferred lactam compounds herein are:
    • [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester;
    • [5R-[5a,6a]]-6-[(R)-1-[(allyloxycarbonyl)oxy]ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester;
    • [5R-[5a,6a]]-6-[(R)-1-[(2,2,2-trichloroethyloxycarbonyl)oxy] ethyl]-3-hydroxymethyl-7-oxo-4-thia-I-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 2,2,2-trichloroethyl ester;
    • [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid diphenylmethyl ester;
    • [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid t-butyl ester;
    • [5R-[4b,5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-4-methyl-7-oxo-1-azabicyclo[3.Z.0]hept-2-ene-2-carboxylic acid allyl ester;
    • [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-(2-hydroxyethylthio)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester; or
    • [5R-[4b,5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-(2-hydroxyethylthio)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester.
  • Preferred lactam moieties, quinolone moieties, and QLAs are described in the following documents: EP-A-0 366,189, White and Demuth, published May 2, 1990; EP-A-0 335, 297, Albrecht et al., published October 4, 1989; and U.S. Patent Application Serial No. 07/511,483, Demuth and White, filed April 18, 1990.
    • Methods of Manufacture
  • The processes of this invention comprise the steps of:
    • (1) Reacting a lactam compound of the formula B-L2-H with phosgene to form an intermediate compound of the formula B-L2-C(=O)-Cl ; and
    • (2) Coupling said intermediate compound with a quinolone compound of the formula Q-L1-R44; wherein R44 is hydrogen, Si(R45)3, or Sn(R45)3; and R45 is lower alkyl.
    and additionally comprise steps for protecting the lactam and quinolone compounds prior to the reacting and coupling steps. In particular, the carboxylate groups at R4 and R13 are protected, using an ester group. The compound formed following the coupling step is then deprotected, by removal of the ester groups, to yield the free acid compound.
  • Accordingly, the process of this invention additionally comprises:
    • (a) a step, prior to said reacting step, wherein an ester of said lactam compound is formed;
    • (b) a step, prior to said coupling step, wherein an ester of said quinolone compound is formed; and
    • (b) deprotection steps, after said coupling step, wherein said groups are removed, wherein said reacting step and said coupling step are performed at a temperature of from about -80°C to about -40°C.
    Suitable hydrolyzable esters useful in such protection steps are well known in the art. They include, for example, allyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, methyl, ethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-methylthioethyl, trimethylsilyl, t-butyldiphenylsilyl, t-butyl, and tributylstannyl esters. Such esters, and suitable protection and deprotection chemistry for carboxylates and other functional groups, are described in T. W. Greene, Protective Groups in Organic Synthesis, J. Wiley and Sons (1981).
  • Further, depending on the specific lactam compounds and quinolone compounds employed, other functional groups (e.g., the R10 substituent or the lactam compound) may need to be protected or blocked in order to prevent undesired competing side reactions from occurring during the coupling step. Protecting groups for hydroxyl substituents include ethers, esters, and carbonates; and protecting groups for amino substituents include carbamates, and amides. If various protecting groups are employed, then an appropriate deprotecting step, that will not decompose the coupled conjugate, may be required to obtain antibacterially active products. Chemistry useful in the protecting and deprotecting steps are well known in the chemical literature.
  • In a preferred process, a silylated quinolone compound is used in the coupling step, wherein R44 of the quinolone compound is Si(R45)3, and R45 is lower alkyl. Preferably R45 is methyl or ethyl. Also, the R45 groups may be independently selected, such that the Si(R45)3 moiety need not contain three identical R45 substituents.
  • Any of a number of silylating reagents known in the art may be used to form the silylated quinolone compound, by reacting the silylating agent with a quinolone compound wherein R44 is hydrogen. Such silylating reagents include, for example, chlorotrimethylsilane; N-methyl-N-trimethylsilyl-trifluoroacetamide; N,N-bis(trimethylsilyl)urea; 1-trimethylsilylimidazole; bis(trimethylsilyl)trifluoroacetamide; and N,O-bis(trimethylsilyl)acetamide. Further, use of the silylating agent to form a silylated quinolone compound may also yield a silyl ester of R4 carboxylate of the quinolone, as a protecting group. This ester can then be removed, using well-known deprotection chemistry.
  • The reacting step and coupling step are carried out in solution, using any of a variety of suitable solvents. Such solvents include, for example: halocarbon solvents, such as methylene chloride, chloroform, and dichloroethane; ethers, such as diethyl ether and tetrahydrofuran (THF); aromatic solvents, such as benzene and toluene; and mixtures thereof. Halocarbon solvents are preferred. Preferably the coupling step comprises adding a solution containing the quinolone compound to a solution containing the intermediate compound.
  • The reacting step and coupling step are conducted at low temperatures, from about -80° C to about -40° C. Preferably, reagents are mixed in the reaction step and coupling step so as to allow control of the temperature within these ranges.
  • Procedures for making a broad variety of lactam and quinolone starting materials are well known in the art. For example, procedures for preparing lactam-containing moieties are described in the following references (including articles cited within these references): Cephalosporins and Penicillins: Chemistry and Biology (E. H. Flynn, ed, 1972) Chapters 2, 3, 4, 5, 6, 7, 15 and Appendix I; Recent Advances in the Chemistry of β-Lactam Antibiotics (A.G. Brown and S. M. Roberts, ed., 1985); Topics in Antibiotic Chemistry, Vol. 3, (Part B) and Vol. 4, (P. Sommes, ed., 1980); Recent Advances in the Chemistry of β-lactam Antibiotics (J. Elks, ed., 1976); Structure-Activity Relationships Among the Semisynthetic Antibiotics (D. Perlman, ed, 1977); Chapts. 1, 2, 3, 4; Antibiotics, Chemotherapeutics and Antibacterial Agents for Disease Control (M. Grayson, ed, 1982); Chemistry and Biology of β-Lactam Antibiotics, Vols 1-3 (K. B. Morin and M. Gorman, eds, 1982); 4 Medicinal Research Reviews 1-24 (1984); 8 Medicinal Research Review 393-440 (1988); 24 Angew. Chem. Int. Ed. Engl. 180-202 (1985); 40 J. Antibiotics 182-189 (1987); EP-A-0,266,060; 42 J. Antibiotics 993 (1989); US-A-4,742,053; 35 Chem. Pharm. Bull. 1903-1909 (1987); 32 J. Med. Chem., 601-604 (1989); US-A-4,791,106; Japanese Patent Publication 62/158291; 31 J. Med. Chem. 1987-1993 (1988); 30 J. Med. Chem., 514-522 (1987); 28 Tet. Let. 285-288 (1987); 28 Tet. Let. 289-292 (1987); 52 J. Org. Chem., 4007-4013 (1987); 40 J. Antibiotics, 370-384 (1987); 40 J. Antibiotics, 1636-1639 (1987); 37 J. Antibiotics, 685-688 (1984); 23 Heterocycles, 2255-2270; 27 Heterocycles, 49-55; 33 Chem. Pharm. Bull. 4371-4381 (1985); 28 Tet. Let, 5103-5106 (1987); 53 J. Org. Chem., 4154-4156 (1988); 39 J. Antibiotics, 1351-1355 (1986); 59 Pure and Appl. Chem., 467-474 (1987); 1987 J.C.S. Chem. Comm.; 44 Tetrahedron, 3231-3240 (1988); 28 Tet. Let., 2883-2886, (1987); 40 J. Antibiotics, 1563-1571 (1987); 33 Chem. Pharm. Bull., 4382-4394 (1985); 37 J. Antibiotics, 57-62 (1984); U.S. Patent 4,631,150; 34 Chem. Pharm. Bull., 999-1014 (1986); 52 J. Org. Chem., 4401-4403 (1987); 39 Tetrahedron, 2505-2513 (1983); 38 J. Antibiotics, 1382-1400 (1985); European Patent Application 053,815; 40 J. Antibiotics, 1563-1571 (1987); 40 J. Antibiotics, 1716-1732 (2987); 47 J. Org. Chem., 5160-5167 (1981); US-A-4,777,252; US-A-4,762,922; EP-A-0 287,734; US-A-4,762,827; EP-A-0,282,895; EP-A-0,282,365; and US-A-4,777,673.
  • General procedures for preparing quinolone compounds useful in the methods of this invention are described in the following references, (including articles listed within these references); 21 Progress in Drug Research, 9-104 (1977); 31 J. Med. Chem., 503-506 (1988); 32 J. Med. Chem., 1313-1318 (1989); 1987 Liebigs Ann. Chem., 871-879 (1987); 14 Drugs Exptl. Clin. Res., 379-383 (1988); 31 J. Med. Chem., 983-991 (1988); 32 J. Med. Chem., 537-542 (1989); 78 J. Pharm. Sci., 585-588 (1989); 26 J. Het. Chem., (1989); 24 J. Het. Chem., 181-185 (1987); US-A-4,599,334, 35 Chem. Pharm. bull., 2281-2285 (1987); 29 J. Med. Chem., 2363-2369 (1986); 31 J. Med. Chem., 991-1001 (1988); 25 J. Het. Chem., 479-485 (1988); EP-A-0,266,576; EP-A-0,251,308, 36 Chem. Pharm. Bull., 1223-1228 (1988); EP-A-0,277,088; EP-A-0,277,039; EP-A-0,228,661; 31 J. Med. Chem., 1586-1590 (1988); 31 J. Med. Chem., 1598-1611 (1988); and 23 J. Med. Chem., 1358-1363 (1980). Preparation of quinolone compounds useful herein are also described in: EP-A-0,366,189, White and Demuth, published May 2, 1990; EP-A-0,335, 297, Albrecht et al., published October 4, 1989; and U.S. Patent Application Serial No. 07/511,483, Demuth and White, filed April 18, 1990.
  • The following non-limiting examples illustrate the processes of the present invention.
    • EXAMPLE 1
  • Preparation of [5R-[5a,6a]]-3-[[[4-(3-Carboxy-1-cyclopropyl-6--fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl] carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid Disodium Salt
    Figure imgb0024
    Figure imgb0025
  • A 3-neck, 1 L flask is fitted with a low temperature thermometer, overhead stirrer and a 500 mL dropping funnel. The apparatus is dried and then cooled to approximately -78° C under nitrogen with a dry ice/acetone bath. Phosgene (60 mL, 20% in toluene) is added via syringe through the dropping funnel. Dichloromethane is then rinsed through the dropping funnel into the flask. A solution of [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyl-oxy)ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid allyl ester (40 gram) and N,N-diisopropylethylamine (20 mL) in 150 mL dichloromethane is transferred via cannula to the dropping funnel on the 1 L flask. This solution is then added to the phosgene solution at such a rate as to maintain the solution temperature between -75° C and -70° C (approximately 2.5 hour). Separately, N-methyl-N-trimethylsilyl-trifluoroacetamide (56 mL) is added to a suspension of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid (33.2 gram) in 250 mL dichloromethane at room temperature. The resulting solution is transferred to the dropping funnel on the 1 L flask via cannula and is added to the reaction mixture at such a rate so as to maintain the reaction temperature between -75° C and -70° C over approximately 1.5 hour. The reaction mixture is stirred for approximately 15 minutes, the cooling bath is removed and 50 mL of water is added, allowing the solution to warm to approximately -10° C. A second aliquot of water (50 mL) is added and the mixture is further warmed to 10° C.
  • The solution is filtered, extracted with water, washed with brine, dried over sodium sulfate and concentrated to approximately 200 mL volume in vacuo. With overhead stirring, methanol (approximately 400 mL) is added to the resulting solution causing an immediate precipitation of an off-white solid. After stirring 15 minutes, the solid is filtered, washed with methanol, then ether and dried under high vacuum to yield approximately 57 gram product I.
  • To a mixture of product I (26 gram) in 360 mL THF containing 19 mL acetic acid at room temperature is rapidly added a solution of tetrabutylammonium fluoride hydrate (32 gram) in 640 mL THF. The reaction is stirred for 24 hours and concentrated to dryness in vacuo. The residue is dissolved in dichloromethane (400 mL), extracted twice with water, washed with brine, dried over sodium sulfate, filtered and concentrated to approximately 250 mL. The solution is diluted with an equal volume of diethyl ether to precipitate the product which is collected by filtration and air-dried to yield approximately 18 gram of product II.
  • To a solution of II (5.2 gram) in 500 mL dichloromethane at 0° C is added 0.76 mL water and bis(triphenylphosphine)palladium (II) chloride (0.13 gram) followed by the rapid addition of tributyltin hydride (2.8 mL). The solution is stirred for 35 minutes at 0° C, then cooled to -7° C to -10° C. Sodium 2-ethylhexanoate (2.6 gram) in 250 mL THF is then added dropwise over 30 minutes. The mixture is stirred an additional 15 minutes and the precipitated product is collected by filtration. The crude solid is stirred in 60 mL acetone for one hour, collected by centrifugation and dried in vacuo to yield 5 gram of the title compound.
  • The following QLAs are also prepared, according to the procedure of the above Example, with substantially similar results.
    Figure imgb0026
    Figure imgb0027
    Figure imgb0028
    Figure imgb0030
    Figure imgb0031
    Figure imgb0032
    Figure imgb0033
    Figure imgb0034
    Figure imgb0035
    Figure imgb0036
    Figure imgb0037
    Figure imgb0038
    Figure imgb0039
    Figure imgb0040
    • EXAMPLE 2
  • Preparation of [5R-[5a,6a]]-3-[[[[1-(3-Carboxy-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridin-7-yl)-pyrrolidin-3-yl]amino]carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid Disodium Salt
    Figure imgb0041
    Figure imgb0042
  • To a solution of 20% phosgene in toluene (1.3 mL) in 11 mL dichloromethane with diisopropylethylamine (0.48 mL) at -35° C to -45° C under a nitrogen atmosphere is added dropwise a solution of [5R-[4b,5a,6a]]-6-[(R)-1-(t-butyldimethylsilyl-oxy)ethyl]-3-hydroxymethyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester (1.0 gram) in 11 mL dichloromethane. The reaction is stirred 1 hour at -35° C to -45° C, then cooled to -78° C. A chilled (-40° C) solution of the 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid allyl ester (1.1 gram) with diisopropylethylamine (0.48 mL) in 23 mL dichloromethane is added by cannula while maintaining the solution temperature below -70° C. After 30 min. the reaction mixture is extracted with cold 0.1 N HCl and water. The dichloromethane layer is dried over sodium sulfate and the solvent evaporated under vacuum. The residue was triturated with hexanes to yield approximately 1.8 gram of product I.
  • To a room temperature solution of product I (2.2 gram) in 40 mL of THF with 1.4 mL of acetic acid is added tetrabutylammonium fluoride hydrate (2.3 gram) in 17 mL of THF dropwise. The mixture is stirred for 24 hours at room temperature under nitrogen atmosphere. The solvent is evaporated under vacuum, the residue is taken up in 50 mL dichloromethane and is washed with water and brine. The dichloromethane layer is dried over sodium sulfate and evaporated in vacuo. The residue is triturated with hexanes and the solid filtered, ground by mortar and pestle in ether, and then further triturated with ether. The solid is filtered to yield 0.80 gram of product II.
  • To a solution of product II (0.5 gram) in 40 mL of dichloromethane with bis(triphenylphosphine) palladium(II) chloride (0.019 gram) and 0.060 mL of water at 0° C under a nitrogen atmosphere is added tributyltin hydride (0.46 mL) and the mixture allowed to stir for 30 min. Sodium 2-ethylhexanoate (0.22 gram) in 9.5 mL of THF is added to the above mixture at 0° C very slowly over 20 min. and stirred for an additional 15 min. after the addition is completed. The precipitate is filtered and washed with ether and acetone. The solid is ground by mortar and pestle with acetone and further triturated with acetone. The solid is filtered and triturated with a 1:12 mixture of aqueous isopropanol. The solid is filtered to yield 0.22 gram the title compound.
  • The following QLAs are also prepared, according to the procedure of the above Example, with substantially similar results.
    Figure imgb0043
    Figure imgb0044
    Figure imgb0045
    Figure imgb0046
    Figure imgb0047
    Figure imgb0048
    Figure imgb0049
    Figure imgb0050
    • EXAMPLE 3
  • Preparation of [5R-[4b,5a,6a]]-3-[[[4-(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl]carbonyloxy]methyl]-6-[(R)-1-hydroxyoxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic Acid Disodium Salt
    Figure imgb0051
  • A 30 L reactor is fitted with a low temperature thermometer, overhead stirrer is charged with dichloromethane (6 L) and toluene (1.8 L) and cooled to -78° C (internal temperature). Phosgene gas is introduced keeping the temperature below approximately -60° C. After recooling the mixture to -78° C, a solution of [5R-[4b,5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept -2-ene-2-carboxylic acid allyl ester (1.2 kg) and N,N-diisopropylethylamine (580 mL) in 4.5 L dichloromethane is added to the reaction via metering pump at such a rate as to maintain the solution temperature between -75° C and -70° C. A premixed solution of N-methyl-N-trimethylsilyl-trifluoroacetamide (1.7 L) and 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid (1 kg) in 7.5 L dichloromethane is then added to the reaction mixture at such a rate as to maintain the reaction temperature between -75° C and -70° C. The reaction mixture is stirred for approximately 15 minutes and 1.5 L of water is added, allowing the solution to warm to approximately -10° C. A second aliquot of water (1.5 L) is added and the mixture is further warmed to approximately 10° C. The solution is filtered, extracted with water, washed with brine, dried over sodium sulfate and concentrated to approximately 6 L volume. With overhead stirring, methanol (3.2 L) is added to the resulting solution causing an immediate off-white precipitate. After stirring 15 minutes, the solid is filtered, washed with methanol, then ether and dried to yield approximately 2.1 kg product I.
  • A 30 L reactor is charged with THF (5.3 L), tetrabutylammonium fluoride (3.22 L, 1 M in THF) and acetic acid (790 mL). Solid product I (870 gram) is added at room temperature with overhead stirring and the resulting suspension is stirred under nitrogen for 20-24 hours. The reaction mixture becomes homogenous overnight. Water (20 L) is added to the reactor, the resulting suspension stirred for one hour, and then the product is filtered. The crude product is placed into the 30 L reactor, more water (20 L) is added, the suspension is stirred for 1 h, and then the product is refiltered, washed with THF (5 L), and then dried to give approximately 550 gram of product II.
  • A 30 L reactor equipped with an overhead stirrer is charged with product II (200 gram) and dichloromethane (12 L). The flask is purged with nitrogen and tetrakis(triphenyl-phosphine)palladium(0) (18 g) is added. The reaction mixture is cooled to -5° C and a solution of sodium 2-ethylhexanoate (103 g) in THF (6 L) is slowly added to the reaction vessel via a metering pump at such a rate that the internal temperature was maintained between -5° C to 0° C. Stirring of the reaction mixture is continued at - 5° C for another 1.5 hour after completion of addition. The reaction mixture is then centrifuged, the supernatant decanted off, and the product washed with additional dichloromethane (6 L). Following centrifugation and decantation, the product is then washed with additional dichloromethane (6 L). This process of washing, centrifugation, and decantation is repeated twice more. Following the final decantation step, final drying of the product affords 180 grams of the title compound.

Claims (14)

  1. A process for making an antimicrobial compound of the formula

            [Q - L1] - L - [L2 - B]

    wherein
    (I) Q is a structure according to Formula (I)
    Figure imgb0052
     wherein
    (A)
    (1) A1 is N or C(R7); where
    (i) R7 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R8)(R9), and
    (ii) R8 and R9 are, independently, R8a where R8a is hydrogen, alkyl, alkenyl, carbocyclic ring, or heterocyclic ring; or R8 and R9 together comprise a heterocyclic ring including the nitrogen to which they are bonded;
    (2) A2 is N or C(R2); where R2 is hydrogen or halogen;
    (3) A3 is N or C(R5); where R5 is hydrogen;
    (4) R1 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R8)(R9);
    (5) R3 is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring;
    (6) R4 is hydroxy; and
    (7) R6 is hydrogen, halogen, nitro or N(R8)(R9);
    (B) except that
    (1) when A1 is C(R7), R1 and R7 may together comprise a heterocyclic ring including N' and A1;
    (2) when A2 is C(R2), R2 and R3 may together comprise -O-(CH2)n-O-, where n is an integer from 1 to 4;
    (3) when A3 is C(R5), R4 and R5 may together comprise a heterocyclic ring including the carbon atoms to which R4 and R5 are bonded and the carbon atom of Formula (I) to which said carbon atoms are bonded; and
    (4) when A3 is C(R5), R1 and R5 may together comprise a heterocyclic ring including N' and the adjacent carbon to which R5 is bonded;
    (C) and except that one of R1, R6, or R3 must be nil;
    (II) B is a structure according to Formula (II):
    Figure imgb0053
     wherein
    (A) R10 is hydrogen, halogen, alkyl, alkenyl, heteroalkyl, a carbocyclic ring, a heterocyclic ring, R8a-O-, R8aCH=N-, (R8)(R9)N-, R17-C(=CHR20)-C(=O)NH-, R17-C(=NO-R19)-C(=O)NH-, or R18-(CH2)m-C(=O)NH-; where
    (1) m is an integer from 0 to 9;
    (2) R17 is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring;
    (3) R18 is R17, -Y1, or -CH(Y2)(R17);
    (4) R19 is R17, arylalkyl, heteroarylalkyl, -C(R22)(R23)COOH, -C(=O)O-R17, or -C(=O)NH-R17, where R22 and R23 are, independently, R17 or together comprise a carbocyclic ring or a heterocyclic ring including the carbon atom to which R22 and R23 are bonded;
    (5) R20 is R19, halogen, -Y1, or -CH(Y2)(R17);
    (6) Y1 is -C(=O)OR21, -C(=O)R21, -N(R24)R21, -S(O)pR29, or -OR29; and Y2 is Y1 or -OH, -SH, or -SO3H;
    (a) p is an integer from 0 to 2;
    (b) R24 is hydrogen; alkyl; alkenyl; heteroalkyl; heteroalkenyl; a carbocyclic ring; a heterocyclic ring; -SO3H; -C(=O)R25; or, when R18 is -CH(N(R24)R21)(R17), R24 may comprise a moiety bonded to R21 to form a heterocyclic ring; and
    (c) R25 is R17, NH(R17), N(R17)(R26), O(R26), or S(R26); where R26 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or when R25 is N(R17)(R26), R26 may be a moiety bonded to R17 to form a heterocyclic ring; and
    (7) R21 is R29 or hydrogen; where R29 is alkyl; alkenyl; arylalkyl; heteroalkyl; heteroalkenyl; heteroarylalkyl; a carbocyclic ring; a heterocyclic ring; or, when Y is N(R24)R21 and R21 is R29, R21 and R24 may together comprise a heterocyclic ring including the nitrogen atom to which R24 is bonded;
    (B) R11 is hydrogen, halogen, alkoxy, or R27C(=O)NH-, where R27 is hydrogen or alkyl;
    (C) bond "a" is a single bond or is nil; and bond "b" is a single bond, a double bond, or is nil; except bond "a" and bond "b" are not both nil;
    (D) R12 is
    Figure imgb0054
     where R28 is
    Figure imgb0055
     and R28 is directly bonded to N" in Formula (II) to form a 5-membered ring; except, if bond "a" is nil, then R12 is
    (1) -C(R8a)(X1)-, where
    (i) X1 is -R21; -OR30; -S(O)rR30, where r is an integer from 0 to 2; -OC(=O)R30; or N(R30)R31; and
    (ii) R30 and R31 are, independently, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituents; or R30 and R31 together comprise a heterocyclic ring including the nitrogen atom to which R30 and R31 are bonded; or
    (2) -CH2-R32-; where R32 is
    Figure imgb0056
     -O-, or
    Figure imgb0057
     and R32 is directly bonded to N" in Formula (II) to form a 5-membered ring;
    (E)
    (1) if bond "b" is a single bond, R13 is -CH(R33)-; or, -C(O)NHSO2-, if bond "a" is nil; or
    Figure imgb0058
     if R14 contains a R36 moiety; where R33 is hydrogen or COOH, and C* is linked to R36 to form a 3-membered ring;
    (2) if bond "b" is a double bond, R13 is -C(R33)=; or
    (3) if bond "b" is nil, R13 is hydrogen, -SO3H, -PO(OR34)OH, -C(O)NHSO2N(R34)(R35), -OSO3H, -CH(R35)COOH, or -OCH(R34)COOH; where R34 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R35 is hydrogen, alkyl, alkenyl, or -NHR8a; or, if R13 is -C(O)NHSO2N(R34)(R35), R34 and R35 may together comprise a heterocyclic ring including the nitrogen to which R34 and R35 are bonded; and
    (F)
    (1) if bond "a" or bond "b" is nil, then R14 is nil;
    (2) if bond "a" and "b" are single bonds, R14 is
    Figure imgb0059
     or
    (3) if bond "a" is a single bond and bond "b" is a double bond, R14 is
    Figure imgb0060
    Figure imgb0061
     where
    (a) W is O; S(O)s, where s is an integer from 0 to 2; or C(R8a)R38), where R38 is hydrogen, alkyl or alkoxy;
    (b) W' is O; or C(R8a)(R38);
    (c) R36 hydrogen; alkyl; alkenyl; -COOH; or, if R13 is
    Figure imgb0062
     R36 may be linked to C* to form a 3-membered carbocyclic ring;
    (d) R37 and is nil, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and
    (e) C"' is directly bonded to R13 to form a 5- or 6-membered ring; and
    (III)
    (A) L is -C(=O)-, and is bonded to L3 and L4
    (B) L1 is L3 or R15L3; where
    (1) L3 is NH;
    (2) R15 is alkyl, alkenyl, heteroalkyl, a heterocyclic ring, a carbocyclic ring, or R15 together with L3 is a heteroalkyl or a heterocyclic ring; and
    (3) L1 is bonded to Q at the point of attachment of R1, R6 or R3, whichever is nil;
    (C) L2 is L4, -X2 t-R39-L4, or -X3 t-R39-L4; where
    (1) L4 is oxygen;
    (2) X2 is oxygen, or S(O)v, where v is 0, 1, or 2;
    (3) X3 is nitrogen; N(R40); N+(R41)(R42); or R43-N(R41); and is linked to R14 by a single or double bond; or, if R14 is nil, X3 is linked to B by a single or double bond; where
    (a) R40 is R8a; -OR8a; or -C(=O)R8a;
    (b) R41 and R42 are, independently, hydrogen; alkyl; alkenyl; carbocyclic rings; heterocyclic rings;
    (c) R43 is N(R41), oxygen or sulfur;
    (4) t is 0 or 1;
    (5) R39 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring; and
    (6)
    (a) if bond "a" or bond "b" is nil, then L2 is bonded directly to R12 or R13; or
    (b) if bond "a" and bond "b" are not nil, then L2 is bonded to R14;
    and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof;
    comprising the steps of:
    (1) Reacting a lactam compound of the formula B-L2-H with phosgene to form an intermediate compound of the formula B-L2-C(=O)-Cl; and
    (2) Coupling said intermediate compound with a quinolone compound of the formula Q-L1-R44; wherein R44 is hydrogen, Si(R45)3, or Sn(R45)3; and R45 is lower alkyl.
    and additionally comprising
    (a) a step, prior to said reacting step, wherein an ester of said lactam compound is formed;
    (b) a step, prior to said coupling step, wherein an ester of said quinolone compound is formed; and
    (c) deprotection steps, after said coupling step, wherein said esters are removed,
    wherein said reacting step and said coupling step are performed at a temperature of from about -80°C to about -40°C.
  2. A process, according to Claim 1, wherein said coupling step comprises adding a solution containing said quinolone compound to a solution containing said intermediate compound.
  3. A process, according to Claim 2, wherein said solutions are in a halocarbon solvent.
  4. A process, according to Claim 3, wherein said halocarbon solvent is selected from methylene chloride, chloroform, dichloroethane, and mixtures thereof.
  5. A process, according to Claim 3, wherein R44 is Si(R45)3.
  6. A process, according to Claim 3, wherein R14 is
    Figure imgb0063
  7. A process, according to Claim 6, wherein W is S(O)s.
  8. A process, according to Claim 7, wherein A1 is C(R7), A2 is C(R2), and A3 is C(R5); or A1 is nitrogen, A2 is C(R2), and A3 is C(R5).
  9. A process, according to Claim 8, wherein A1 is C(R7), A2 is C(R2), and A3 is C(R5).
  10. A process, according to Claim 8, wherein R3 is nil and comprises a bond to L1.
  11. A process, according to Claim 8, wherein R6 is nil and comprises a bond to L1.
  12. A process, according to Claim 8, wherein said quinolone compound is:
    1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid;
    1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid allyl ester;
    1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid diphenylmethyl ester;
    1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid t-butyl ester;
    1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid 2,2,2-trichloroethyl ester;
    7-(3-Amino.1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro--4-oxo-quinoline-3-carboxylic acid;
    15 7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro -4-oxo-quinoline-3-carboxylic acid allyl ester;
    5-Amino-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4 20 -dihydro-4-oxo-quinoline-3-carboxylic acid allyl ester;
    5-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-piperazinyl)-4-oxo-quinoline-3-carboxylic acid;
    7-(3-Amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid allyl ester; or
    27-[3-(t-Butyloxycarbonyl)amino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-hydrazino-4-oxo-quinoline-3-carboxylic acid allyl ester.
  13. A process, according to Claim 8, wherein lactam compound is:
    [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester;
    [5R-[5a,6a]]-6-[(R)-1-[(allyloxycarbonyl)oxy]ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester;
    [5R-[5a,6a]]-6-[(R)-1-[(2,2,2-trichloroethyloxycarbonyl)oxy] 10 ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 2,2,2-trichloroethyl ester;
    [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid diphenylmethyl ester;
    [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid t-butyl ester;
    [5R-[4b,5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-hydroxymethyl-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester;
    [5R-[5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-(2-hydroxyethylthio)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester; or
    [5R-[4b,5a,6a]]-6-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-3-(2-hydroxyethylthio)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid allyl ester.
  14. A process, according to Claim 1, wherein said antimicrobial compound is:
    [5R-[5a,6a]]-3-[[[4-(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro -4-oxo-7-quinolinyl)-1-piperazinyl]carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3,Z.0]hept-Z-ene-2-carboxylic Acid, Disodium Salt;
    [5R-[4b,5a,6a]]-3-[[[4-(3-Carboxy-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-quinolinyl)-1-piperazinyl]carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid, Disodium Salt;
    [5R-[5a,6a]]-3-[[[1-(3-Carboxy-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-quinolinyl)-(S)-3-pyrrolidinyl]amino]carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabjcyclo[3.2.0]hept-2-ene-2-carboxylic Acid, Disodium Salt;
    [5R-[4b,5a,6a]]-3-[[[[1-(3-Carboxy-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-quinolinyl)-(S)-3-pyrrolidinyl]amino]carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid, Disodium Salt;
    [5R-[5a,6a]]-3-[[[[1-[3-Carboxy-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridin-7-yl]-(S)-3-pyrrolidinyl] amino]-carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid, Disodium Salt;
    [5R-[4b,5a,6a]]-3-[[[[1-[3-Carboxy-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridin-7-yl]-(S)-3-pyrrolidinyl]amino]-carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-I-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid, Disodium Salt;
    [5R-[5a,6a]]-3-[[[4-(5-Amino-3-carboxy-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-quinolinyl)-2,6-dimethyl-1-piperazinyl]carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid, Disodium Salt;
    [5R-[4b,5a,6a]]-3-[[[4-(5-Amino-3-carboxy-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-quinolinyl)-2,6-dimethyl-1-piperazinyl]carbonyloxy]methyl]-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic Acid, Disodium Salt.
EP92920743A 1991-10-01 1992-09-28 Process for making antimicrobial quinolonyl lactams Expired - Lifetime EP0606336B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US76961591A 1991-10-01 1991-10-01
US769615 1991-10-01
PCT/US1992/008246 WO1993007154A1 (en) 1991-10-01 1992-09-28 Process for making antimicrobial quinolonyl lactams

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EP0606336A1 EP0606336A1 (en) 1994-07-20
EP0606336B1 true EP0606336B1 (en) 1997-03-19

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EP92920743A Expired - Lifetime EP0606336B1 (en) 1991-10-01 1992-09-28 Process for making antimicrobial quinolonyl lactams

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US (1) US5281703A (en)
EP (1) EP0606336B1 (en)
KR (1) KR100253825B1 (en)
CN (1) CN1046523C (en)
AT (1) ATE150463T1 (en)
AU (1) AU667837B2 (en)
BR (1) BR9206590A (en)
CA (1) CA2120493A1 (en)
CZ (1) CZ73194A3 (en)
DE (1) DE69218445T2 (en)
DK (1) DK0606336T3 (en)
ES (1) ES2101119T3 (en)
FI (1) FI941490L (en)
GR (1) GR3023227T3 (en)
HU (1) HUT67423A (en)
MX (1) MX9205620A (en)
NO (1) NO304599B1 (en)
NZ (1) NZ244557A (en)
PT (1) PT100920B (en)
RU (1) RU2130938C1 (en)
SK (1) SK37594A3 (en)
WO (1) WO1993007154A1 (en)

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US5646163A (en) * 1992-10-30 1997-07-08 The Procter & Gamble Company Quinolone 5-(N-heterosubstituted amino) antimicrobials
DE69431684T2 (en) * 1993-12-28 2003-03-20 Kao Corp., Tokio/Tokyo Crosslinked cellulosic fibers, absorbent papers and absorbent elements, topsheet and absorbent articles, which fibers are used
EP0775114B1 (en) * 1994-08-02 2000-03-22 The Procter & Gamble Company Process for making antimicrobial compounds
JPH10503521A (en) * 1994-08-02 1998-03-31 ザ、プロクター、エンド、ギャンブル、カンパニー Method for producing quinolonyl lactam antimicrobial agent and novel intermediate compound
EP0695753A1 (en) * 1994-08-05 1996-02-07 Zeneca Limited Carbapenem derivatives containing a bicyclic substituent, process for their preparation, and their use
US5607928A (en) * 1994-08-05 1997-03-04 Zeneca Limited Carbapenem derivatives containing a bicyclic ketone substituent and their use as anti-infectives
US5693791A (en) * 1995-04-11 1997-12-02 Truett; William L. Antibiotics and process for preparation
EP0970065A4 (en) * 1997-11-29 2001-03-07 William L Truett Antibiotics and process for preparation
US6437119B1 (en) 1998-05-07 2002-08-20 William Lawrence Truett Compounds formed from two or three antibiotics and their processes of preparation
US6638908B1 (en) * 2000-08-09 2003-10-28 Yale University Crystals of the large ribosomal subunit
US6947844B2 (en) * 2000-08-09 2005-09-20 Yale University Modulators of ribosomal function and identification thereof
IN191798B (en) 2000-11-03 2004-01-03 Ranbaxy Lab Ltd
DE60101724T2 (en) 2001-03-30 2004-12-02 Dar Al Dawa Development, And Investment Co. Quinolin-4-one derivatives and their use as antibiotics
IL151012A0 (en) * 2001-08-03 2003-02-12 Ribosomes Structure And Protei Ribosomes structure and protein synthesis inhibitors
US6952650B2 (en) 2001-08-03 2005-10-04 Yale University Modulators of ribosomal function and identification thereof
US7091196B2 (en) 2002-09-26 2006-08-15 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using same
AU2004217919A1 (en) * 2003-03-05 2004-09-16 Rib-X Pharmaceuticals, Inc. Bifunctional heterocyclic compounds and methods of making and using the same
WO2005042554A1 (en) * 2003-10-30 2005-05-12 Rib-X Pharmaceuticals, Inc. Bifunctional macrolide heterocyclic compounds and methods of making and using the same
US20070270357A1 (en) * 2003-11-18 2007-11-22 Farmer Jay J Bifunctional Macrolide Heterocyclic Compounds and Methods of Making and Using the Same
EP1723159B1 (en) 2004-02-27 2019-06-12 Melinta Therapeutics, Inc. Macrocyclic compounds and methods of making and using the same

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HUT49889A (en) * 1988-03-31 1989-11-28 Hoffmann La Roche Process for producing acyl derivatives
EP0366641B1 (en) * 1988-10-24 2000-07-05 Norwich Eaton Pharmaceuticals, Inc. Novel antimicrobial quinolonyl lactam esters
EP0366193A3 (en) * 1988-10-24 1992-01-08 Norwich Eaton Pharmaceuticals, Inc. Novel antimicrobial quinolonyl lactams
EP0997466A1 (en) * 1988-10-24 2000-05-03 PROCTER & GAMBLE PHARMACEUTICALS, INC. Novel antimicrobial lactam-quinolones
SG54293A1 (en) * 1988-10-24 1998-11-16 Procter & Gamble Pharma Novel antimicrobial fluoroquinolonyl cephems
ZA912279B (en) * 1990-04-09 1992-02-26 Hoffmann La Roche Carbapenem compounds
DE69132256T2 (en) * 1990-04-18 2001-01-25 Procter & Gamble Pharmaceuticals, Inc. ANTIMICROBIAL CHINOLONYL LACTAME

Also Published As

Publication number Publication date
DE69218445D1 (en) 1997-04-24
BR9206590A (en) 1995-04-25
DK0606336T3 (en) 1997-04-14
AU667837B2 (en) 1996-04-18
WO1993007154A1 (en) 1993-04-15
FI941490A7 (en) 1994-05-02
CN1046523C (en) 1999-11-17
MX9205620A (en) 1993-12-01
AU2693892A (en) 1993-05-03
ES2101119T3 (en) 1997-07-01
NZ244557A (en) 1996-02-27
CZ73194A3 (en) 1994-11-16
HUT67423A (en) 1995-04-28
DE69218445T2 (en) 1997-08-07
ATE150463T1 (en) 1997-04-15
FI941490A0 (en) 1994-03-30
NO941108L (en) 1994-05-31
SK37594A3 (en) 1995-02-08
CA2120493A1 (en) 1993-04-15
KR100253825B1 (en) 2000-05-01
US5281703A (en) 1994-01-25
RU2130938C1 (en) 1999-05-27
PT100920A (en) 1993-10-29
NO304599B1 (en) 1999-01-18
FI941490L (en) 1994-05-02
PT100920B (en) 1999-07-30
NO941108D0 (en) 1994-03-25
GR3023227T3 (en) 1997-07-30
HU9400940D0 (en) 1994-06-28
CN1075146A (en) 1993-08-11
EP0606336A1 (en) 1994-07-20

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